In collaboration with colleagues at the Kitasato Institute (Japan), we recently determined the complete relative and absolute stereochemistry of chloropeptins I and II. These novel macrobicyclic heptapeptides inhibit the binding of the HIV gp120 envelope glycoprotein to the cluster determinant 4 (CD4) receptor of T-cell lymphocytes, a critical event in HIV infection leading to the onset of AIDS. Inhibitors of gp120-CD4 binding hold considerable promise an anti-HIV therapeutic agents. The principal goals of this research program are: (A) to devise an efficient, stereocontrolled total synthesis of chloropeptin I, focusing on atrodiastereoselectiove construction of the unique, axially chiral biaryl linkage; and (B) to design, synthesize, and test analogs of the chloropeptins in order to optimize the inhibition of gp-120-CD4 binding.